Studying the T Cell-Astrocyte Immune Synapse

Our current quantitative knowledge of the kinetics of antibody-mediated immunity is partly based on idealized experiments throughout the last decades. However, new experimental techniques often render contradictory quantitative outcomes that shake previously uncontroversial assumptions. This has been the case in the field of T-cell receptors, where recent techniques for measuring the 2-dimensional rate constants of T-cell receptor–ligand interactions exposed results contradictory to those obtained with techniques measuring 3-dimensional interactions. Recently, we have developed a mathematical framework to rationalize those discrepancies, focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of “catch bonds” and on the recent observations that B-cell synapses retract and pull antigen generating a “retracting force”, and propose some testable predictions that can lead to future research.

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Ca2+/Calmodulin-Dependent Protein Kinase II Is a Modulator of CARMA1-Mediated NF-κB Activation

Molecular and Cellular Biology ◽

10.1128/mcb.02469-05 ◽

2006 ◽

Vol 26 (14) ◽

pp. 5497-5508 ◽

Cited By ~ 72

Author(s):

Kazuhiro Ishiguro ◽

Todd Green ◽

Joseph Rapley ◽

Heather Wachtel ◽

Cosmas Giallourakis ◽

...

Keyword(s):

T Cell ◽

Protein Kinase ◽

T Cell Activation ◽

Cell Activation ◽

Cell Receptor ◽

Tcr Signaling ◽

Dependent Protein Kinase ◽

Immune Synapse ◽

Protein Kinase Ii ◽

Dependent Protein

ABSTRACT CARMA1 is a central regulator of NF-κB activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF-κB signaling downstream of the T-cell receptor (TCR). Computational analysis of expression neighborhoods of CARMA1-Bcl10MALT 1 for enrichment in kinases identified calmodulin-dependent protein kinase II (CaMKII) as an important component of this pathway. Here we report that Ca2+/CaMKII is redistributed to the immune synapse following T-cell activation and that CaMKII is critical for NF-κB activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF-κB activation. Moreover, we have shown that CaMKII phosphorylates CARMA1 on Ser109 and that the phosphorylation facilitates the interaction between CARMA1 and Bcl10. These results provide a novel function for CaMKII in TCR signaling and CARMA1-induced NF-κB activation.

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Removal of C-Terminal Src Kinase from the Immune Synapse by a New Binding Protein

Molecular and Cellular Biology ◽

10.1128/mcb.25.6.2227-2241.2005 ◽

2005 ◽

Vol 25 (6) ◽

pp. 2227-2241 ◽

Cited By ~ 27

Author(s):

Souad Rahmouni ◽

Torkel Vang ◽

Andres Alonso ◽

Scott Williams ◽

Marianne van Stipdonk ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Interleukin 2 ◽

Antigen Receptor ◽

T Cell Antigen Receptor ◽

Intracellular Location ◽

Immune Synapse ◽

Cell Antigen Receptor ◽

Cell Antigen

ABSTRACT The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells. Engagement of the T-cell antigen receptor results in a removal of Csk from the lipid raft-associated transmembrane protein PAG/Cbp. Instead, Csk becomes associated with an ∼72-kDa tyrosine-phosphorylated protein, which we identify here as G3BP, a phosphoprotein reported to bind the SH3 domain of Ras GTPase-activating protein. G3BP reduced the ability of Csk to phosphorylate Lck at Y505 by decreasing the amount of Csk in lipid rafts. As a consequence, G3BP augmented T-cell activation as measured by interleukin-2 gene activation. Conversely, elimination of endogenous G3BP by RNA interference increased Lck Y505 phosphorylation and reduced TCR signaling. In antigen-specific T cells, endogenous G3BP moved into a intracellular location adjacent to the immune synapse, but deeper inside the cell, upon antigen recognition. Csk colocalization with G3BP occurred in this “parasynaptic” location. We conclude that G3BP is a new player in T-cell-antigen receptor signaling and acts to reduce the amount of Csk in the immune synapse.

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The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

Science Signaling ◽

10.1126/scisignal.aba0717 ◽

2021 ◽

Vol 14 (687) ◽

pp. eaba0717

Author(s):

Shunsuke Kataoka ◽

Priyanka Manandhar ◽

Judong Lee ◽

Creg J. Workman ◽

Hridesh Banerjee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Transmembrane Domain ◽

Transmembrane Protein ◽

Cell Receptor ◽

Mapk Signaling ◽

Inhibitory Protein ◽

Immune Synapse

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

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Retrograde And Anterograde Transport Of LAT-Vesicles During The Immunological Synapse Formation: Defining The Finely-Tuned Mechanism

10.1101/2020.12.17.423267 ◽

2020 ◽

Author(s):

Juan José Saez ◽

Stéphanie Dogniaux ◽

Massiullah Shafaq-Zadah ◽

Ludger Johannes ◽

Claire Hivroz ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Synapse Formation ◽

Immunological Synapse ◽

Retrograde Transport ◽

Anterograde Transport ◽

Immune Synapse ◽

Cellular Context ◽

Intracellular Compartments

ABSTRACTLAT is an important player of the signaling cascade induced by TCR activation. This adapter molecule is present at the plasma membrane of T lymphocytes and more abundantly in intracellular compartments. Upon T-cell activation the intracellular pool of LAT is recruited to the immune synapse (IS). We previously described two pathways controlling LAT trafficking: retrograde transport from endosomes to the TGN, and anterograde traffic from the Golgi to the IS. We address the specific role of 4 proteins, the GTPase Rab6, the t-SNARE syntaxin-16, the v-SNARE VAMP7 and the golgin GMAP210, in each pathway. Using different methods (endocytosis and Golgi trap assays, confocal and TIRF microscopy, TCR-signalosome pull down) we show that syntaxin-16 is regulating the retrograde transport of LAT whereas VAMP7 is regulating the anterograde transport. Moreover, GMAP210 and Rab6, known to contribute in both pathways, are in our cellular context specifically and respectively involved in anterograde and retrograde transport of LAT. Altogether, our data describe how retrograde and anterograde pathways coordinate LAT enrichment at the IS and point the Golgi as a central hub for the polarized recruitment of LAT to the IS. The role that this finely-tuned transport of signaling molecules plays in T-cell activation is discussed.

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Agent-Based Modeling of T Cell Receptor Cooperativity

International Journal of Molecular Sciences ◽

10.3390/ijms21186473 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6473

Author(s):

Anastasios Siokis ◽

Philippe A. Robert ◽

Michael Meyer-Hermann

Keyword(s):

T Cell ◽

Synapse Formation ◽

Immunological Synapse ◽

Cell Receptor ◽

Agent Based Model ◽

Tcr Signaling ◽

Immune Synapse ◽

Agent Based ◽

Affinity Modulation ◽

Antigen Peptide

Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time and depends on the density of ligands of the antigen peptide presented by major histocompatibility complexes (pMHC) and TCR molecules. A comparison between the presence or absence of TCR–pMHC centrally directed flow due to F-actin coupling suggests that centripetal transport is a potential mechanism for affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model shows that TCR affinity can potentially be actively modulated by positive/negative feedback of the F-actin foci on the TCR-pMHC association rate kon.

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A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells

Blood ◽

10.1182/blood-2005-07-2903 ◽

2006 ◽

Vol 107 (3) ◽

pp. 1010-1017 ◽

Cited By ~ 138

Author(s):

Peta J. O'Connell ◽

Xiangbin Wang ◽

Matilde Leon-Ponte ◽

Corrie Griffiths ◽

Sandeep C. Pingle ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Activated T Cells ◽

Immune Synapse ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

5 Ht Uptake

AbstractAdaptive immunity is triggered at the immune synapse, where peptide-major histocompatibility complexes and costimulatory molecules expressed by dendritic cells (DCs) are physically presented to T cells. Here we describe transmission of the inflammatory monoamine serotonin (5-hydroxytryptamine [5-HT]) between these cells. DCs take up 5-HT from the microenvironment and from activated T cells (that synthesize 5-HT) and this uptake is inhibited by the antidepressant, fluoxetine. Expression of 5-HT transporters (SERTs) is regulated by DC maturation, exposure to microbial stimuli, and physical interactions with T cells. Significantly, 5-HT sequestered by DCs is stored within LAMP-1+ vesicles and subsequently released via Ca2+-dependent exocytosis, which was confirmed by amperometric recordings. In turn, extracellular 5-HT can reduce T-cell levels of cAMP, a modulator of T-cell activation. Thus, through the uptake of 5-HT at sites of inflammation, and from activated T cells, DCs may shuttle 5-HT to naive T cells and thereby modulate T-cell proliferation and differentiation. These data constitute the first direct measurement of triggered exocytosis by DCs and reveal a new and rapid type of signaling that may be optimized by the intimate synaptic environment between DCs and T cells. Moreover, these results highlight an important role for 5-HT signaling in immune function and the potential consequences of commonly used drugs that target 5-HT uptake and release.

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